Proprotein convertase subtilisin/kexin type 9 and lipid metabolism

Spolitu, Stefano; Dai, Wen; Zadroga, John A.; Özcan, Lale

doi:10.1097/mol.0000000000000601

Cited by 32 publications

(19 citation statements)

References 71 publications

(58 reference statements)

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“…Patients confronting these multiple metabolic risk factors may benefit from exploring new therapeutic frontiers achieving the goal of personalized disease management ( Giglio et al, 2021 ). Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors—both monoclonal antibodies and inclisiran—lower Lp(a) by 26%, but this is insufficient for individuals with very high Lp(a) levels ( Spolitu et al, 2019 ). New agents, such as a N-Acetylgalactosamine (GalNAc) linked antisense oligonucleotides (ASO) against Lp(a) (TQJ230, trade name pelacarsen) and a small interfering RNA (siRNA) compound aimed at reducing apo(a) synthesis (AMG 890, trade name olpasiran) reduce Lp(a) levels by 80–90% with no effect on other variables ( Viney et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Assessment of Associations Between Serum Lipoprotein (a) Levels and Atherosclerotic Vascular Diseases in Hungarian Patients With Familial Hypercholesterolemia Using Data Mining and Machine Learning

et al. 2022

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Background and aims: Premature mortality due to atherosclerotic vascular disease is very high in Hungary in comparison with international prevalence rates, though the estimated prevalence of familial hypercholesterolemia (FH) is in line with the data of other European countries. Previous studies have shown that high lipoprotein(a)- Lp(a) levels are associated with an increased risk of atherosclerotic vascular diseases in patients with FH. We aimed to assess the associations of serum Lp(a) levels and such vascular diseases in FH using data mining methods and machine learning techniques in the Northern Great Plain region of Hungary.Methods: Medical records of 590,500 patients were included in our study. Based on the data from previously diagnosed FH patients using the Dutch Lipid Clinic Network scores (≥7 was evaluated as probable or definite FH), we trained machine learning models to identify FH patients.Results: We identified 459 patients with FH and 221 of them had data available on Lp(a). Patients with FH had significantly higher Lp(a) levels compared to non-FH subjects [236 (92.5; 698.5) vs. 167 (80.2; 431.5) mg/L, p < .01]. Also 35.3% of FH patients had Lp(a) levels >500 mg/L. Atherosclerotic complications were significantly more frequent in FH patients compared to patients without FH (46.6 vs. 13.9%). However, contrary to several other previous studies, we could not find significant associations between serum Lp(a) levels and atherosclerotic vascular diseases in the studied Hungarian FH patient group.Conclusion: The extremely high burden of vascular disease is mainly explained by the unhealthy lifestyle of our patients (i.e., high prevalence of smoking, unhealthy diet and physical inactivity resulting in obesity and hypertension). The lack of associations between serum Lp(a) levels and atherosclerotic vascular diseases in Hungarian FH patients may be due to the high prevalence of these risk factors, that mask the deleterious effect of Lp(a).

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Section: Discussionmentioning

confidence: 99%

Assessment of Associations Between Serum Lipoprotein (a) Levels and Atherosclerotic Vascular Diseases in Hungarian Patients With Familial Hypercholesterolemia Using Data Mining and Machine Learning

et al. 2022

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“…Correlation with other proteins of cardiovascular health, including NPPC ( 54, 55 ) and FABP9 ( 56 ), further support this hypothesis. Finally, among the highly correlated proteins was PCSK9 that has a central role not only in LDL metabolism ( 57–59 ) but has been shown to promote platelet activation ( 60 ) and can be found elevated in sepsis ( 61 ). As a result, our findings demonstrate a connection between platelet hyperactivation and elevated markers of cardiovascular dysregulation.…”

Section: Discussionmentioning

confidence: 99%

Signaling through FcγRIIA and the C5a-C5aR pathway mediates platelet hyperactivation in COVID-19

Apostolidis

Sarkar

Giannini

et al. 2021

Preprint

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Patients with COVID-19 present with a wide variety of clinical manifestations. Thromboembolic events constitute a significant cause of morbidity and mortality in patients infected with SARS-CoV-2. Severe COVID-19 has been associated with hyperinflammation and pre-existing cardiovascular disease. Platelets are important mediators and sensors of inflammation and are directly affected by cardiovascular stressors. In this report, we found that platelets from severely ill, hospitalized COVID-19 patients exhibit higher basal levels of activation measured by P-selectin surface expression, and have a poor functional reserve upon in vitro stimulation. Correlating clinical features to the ability of plasma from COVID-19 patients to stimulate control platelets identified ferritin as a pivotal clinical marker associated with platelet hyperactivation. The COVID-19 plasma-mediated effect on control platelets was highest for patients that subsequently developed inpatient thrombotic events. Proteomic analysis of plasma from COVID-19 patients identified key mediators of inflammation and cardiovascular disease that positively correlated with in vitro platelet activation. Mechanistically, blocking the signaling of the FcγRIIa-Syk and C5a-C5aR pathways on platelets, using antibody-mediated neutralization, IgG depletion or the Syk inhibitor fostamatinib, reversed this hyperactivity driven by COVID-19 plasma and prevented platelet aggregation in endothelial microfluidic chamber conditions, thus identifying these potentially actionable pathways as central for platelet activation and/or vascular complications in COVID-19 patients. In conclusion, we reveal a key role of platelet-mediated immunothrombosis in COVID-19 and identify distinct, clinically relevant, targetable signaling pathways that mediate this effect. These studies have implications for the role of platelet hyperactivation in complications associated with SARS-CoV-2 infection.

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“…If LDL-C is still above goal in adult FH patients, bile acid sequestrants or niacin can be used as third-line agents. However, these drugs are poorly tolerated and have limited efficacy in lowering LDL-C. A major breakthrough in the treatment of FH has been the advent of PCSK9-based therapies [ 72 ]. In FH patients with ASCVD or with other major risk factors, treatment with an anti-PCSK9 monoclonal antibody (mAb) is recommended if LDL-C remains above target despite maximally tolerated statin plus ezetimibe [ 50 ].…”

Section: Management Of Fhmentioning

confidence: 99%

Management of Familial Hypercholesterolemia: Current Status and Future Perspectives

Lui

Lee

Tan

2020

Journal of the Endocrine Society

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Familial hypercholesterolemia (FH) is the most common monogenic disorder associated with premature atherosclerotic cardiovascular disease. Early diagnosis and effective treatment can significantly improve prognosis. Recent advances in the field of lipid metabolism have shed light on the molecular defects in FH and new therapeutic options have emerged. A search of PubMed database up to March 2020 was performed for this review using the following keywords: “familial hypercholesterolemia”, “diagnosis”, “management”, “guideline”, “consensus”, “genetics”, “screening”, “lipid lowering agents”. The prevalence rate of heterozygous FH is approximately 1 in 200 to 250 and FH is underdiagnosed and undertreated in many parts of the world. Diagnostic criteria have been developed to aid the clinical diagnosis of FH. Genetic testing is now available but not widely used. Cascade screening is recommended to identify affected family members and the benefits of early interventions are clear. Treatment strategy and target is currently based on LDL cholesterol levels as the prognosis of FH largely depends on the magnitude of LDL cholesterol lowering that can be achieved by lipid-lowering therapies. Statins with or without ezetimibe are the mainstay of treatment and are cost-effective. Addition of newer medications like PCSK9 inhibitors is able to further lower LDL cholesterol levels substantially but the cost is high. Lipoprotein apheresis is indicated in homozygous FH or severe heterozygous FH patients with inadequate response to cholesterol-lowering therapies. In conclusion, FH is a common treatable genetic disorder and although our understanding of this disease has improved, many challenges still remain for its optimal management.

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Proprotein convertase subtilisin/kexin type 9 and lipid metabolism

Cited by 32 publications

References 71 publications

Assessment of Associations Between Serum Lipoprotein (a) Levels and Atherosclerotic Vascular Diseases in Hungarian Patients With Familial Hypercholesterolemia Using Data Mining and Machine Learning

Assessment of Associations Between Serum Lipoprotein (a) Levels and Atherosclerotic Vascular Diseases in Hungarian Patients With Familial Hypercholesterolemia Using Data Mining and Machine Learning

Signaling through FcγRIIA and the C5a-C5aR pathway mediates platelet hyperactivation in COVID-19

Management of Familial Hypercholesterolemia: Current Status and Future Perspectives

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